Cocrystals are crystals that contain two or more non-identical molecules. Examples of cocrystals may be found in the Cambridge Structural Database. Examples of cocrystals may also be found at Etter, Margaret C., and Daniel A. Adsmond (1990) “The use of cocrystallization as a method of studying hydrogen bond preferences of 2-aminopyridine” J. Chem. Soc., Chem. Commun. 1990 589-591, Etter, Margaret C., John C. MacDonald, and Joel Bernstein (1990) “Graph-set analysis of hydrogen-bond patterns in organic crystals” Acta Crystallogr., Sect. B, Struct. Sci. B46 256-262, Etter, Margaret C., Zofia Urba czyk-Lipkowska, Mohammad Zia-Ebrahimi, and Thomas W. Panunto (1990b) “Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas” J. Am. Chem. Soc. 112 8415-8426, which are incorporated herein by reference in their entireties.
The following articles are also incorporated herein by reference in their entireties: Carl Henrik Gorbotz and Hans-Petter Hersleth, 2000, “On the inclusion of solvent molecules in the crystal structures of organic compounds”; Acta Cryst. (2000), B56, 625-534; and V. S. Senthil Kumar, Ashwini Nangia, Amy K. Katz and H. L. Carrell, 2002, “Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1,4,-Dithiane-1,4-dioxide” American Chemical Society, Crystal Growth & Design, Vol. 2, No. 4, 2002.
By cocrystallizing a compound with another compound, referred to as a “coformer”, one creates a new solid form which has unique properties compared with existing solid forms of that compound. For example, a cocrystal may have different dissolution and solubility properties than the compound itself or as a salt. In the pharmaceutical field, the compound is often known as an active pharmaceutical ingredient (“API”), and the other component of the cocrystal (the coformer) is often a pharmaceutically acceptable compound (which could also be an API). Cocrystals containing APIs can be used to deliver APIs therapeutically. New drug formulations comprising cocrystals of APIs with pharmaceutically acceptable coformers may have superior properties over existing drug formulations. Compounds and coformers may also include, by way of example only, nutraceuticals, agricultural chemicals, pigments, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.
When the compound, such as an API, is a hydrochloride (HCl) salt, for example, one can cocrystallize the HCl salt with a neutral coformer molecule. By doing this, one can create a cocrystal with specific properties. For instance one can make a cocrystal comprising an active pharmaceutical ingredient having greater or lesser intrinsic solubility and/or a faster or slower dissolution rate, depending on the coformer compound that is chosen.
By “coformer” what is meant is the component of the cocrystal that is not the compound of the cocrystal. The coformer is present in order to form the cocrystal with the compound. Thus, the coformer is part of the crystal lattice. It is contemplated that one or more coformers may be employed in a cocrystal, according to any of the techniques of the disclosure. Accordingly, the coformer is not required to have an activity of its own, although it may have some activity. In some situations, the coformer may have the same activity as or an activity complementary to that of the compound.
For example, some coformers may facilitate the therapeutic effect of an active pharmaceutical ingredient. For pharmaceutical formulations, the coformer may be any pharmaceutically acceptable molecule that forms a cocrystal with the API or its salt. The Registry of Toxic Effects of Chemical Substances (RTECS) database is a useful source for toxicology information, and the GRAS list contains about 2500 relevant compounds. Both sources may be used to help identify suitable coformers.
The coformer may be non-ionized, such as, for example, benzoic acid, succinic acid, and caffeine, or zwitterionic, such as, for example, L-lysine, L-arginine, or L-proline, or may be a salt, such as, for example, sodium benzoate or sodium succinate. Coformers may include, but are not limited to, organic bases, organic salts, alcohols, aldehydes, amino acids, sugars, ionic inorganics, carboxylic acids, amines, flavoring agents, sweeteners, nutraceuticals, aliphatic esters, aliphatic ketones, organic acids, aromatic esters, alkaloids, and aromatic ketones. In at least certain embodiments, the coformer may be a carboxylic acid or an alkaloid. Typically, coformers will have the ability to form complementary non-covalent interactions with the compound or its salt, including APIs and salts thereof, for example the ability to form hydrogen bonds with the compound or its salt.
Properties of compounds or their salts, such as APIs or salts thereof, may be modified by forming a cocrystal. Such properties include, for example, melting point, density, hygroscopicity, crystal morphology, loading volume, compressibility, and shelf life. Furthermore, other properties such as bioavailability, dissolution, solubility, toxicity, taste, physical stability, chemical stability, production costs, and manufacturing method may be modified by using a cocrystal, rather than the API alone or as a salt.
A compound, such as an API, can be screened for possible cocrystals, for example where polymorphic forms, hydrates, or solvates do not readily form from the compound. For example, a neutral compound that can only be isolated as amorphous material could be cocrystallized. Forming a cocrystal may improve the performance of a drug formulation of an API, for example by changing one or more properties identified earlier. A cocrystal may also optionally be used to isolate or purify a compound during manufacturing. If it is desirable to identify all of the solid state phases of an active pharmaceutical ingredient, then cocrystallization may be particularly desirable.
While much interest has been paid to preparing cocrystals of APIs and other compounds such as nutraceuticals, a recurring challenge has been the ability to prepare cocrystals in sufficient quantity or scale for commercialization. When cocrystals are prepared in a laboratory, techniques, such as with seeds or non-solvent approaches used to screen for the cocrystals, are typically not scalable and yields are in the milligram scale. Further, reports by others have shown thermodynamic and kinetic limitations for using solvent-based approaches. In particular, the inability to obtain congruent dissolution with compounds and coformers in a solvent has been a barrier to successful and reproducible scaled-up manufacture of cocrystals (Chiarella). Such dissolution problems are especially acute when the solubilities of the compound and the coformer differ substantially in the solvent selected. Thus, there is a need to develop a process whereby cocrystals can be scaled-up to at least gram-scale quantities.
By way of example only, both resveratrol and pterostilbene have been reported to exhibit a range of biological activities including anti-cancer, antioxidant, anti-inflammatory and other potential health benefits. Pterostilbene is found in nature in a variety of grapes and berries as well as plants commonly used in traditional folk medicine. Significant interest in pterostilbene has been generated in recent years due to its perceived health benefits, leading to increased consumption of foods that contain the compound such as grapes and berries.
Pterostilbene has, however, been noted to have poor solubility in water, making it difficult to incorporate in food extracts or supplements (“nutraceuticals”) (López-Nicolás, J. M.; Rodriguez-Bonilla, P.; Méndez-Cazorla, L.; Garcia-Carmona, F., Physicochemical Study of the Complexation of Pterostilbene by Natural and Modified Cyclodextrins. Journal of Agricultural and Food Chemistry 2009, 57, (12), 5294-5300.). In addition, pterostilbene exhibits poor bioavailability and is easily oxidized by various enzymes (Pezet, R., Purification and characterization of a 32-kDa laccase-like stilbene oxidase produced by Botrytis cinerea. FEMS Microbiol. Lett. 1998, 167, 203-208 and Breuil, A. C.; Jeandet, P.; Adrian, M.; Chopin, F.; Pirio, N.; Meunier, P.; Bessis, R., Characterization of a pterostilbene dehydrodimer produced by laccase of Botrytis cinerea. Phytopathology 1999, 89, (298-302).). The melting point has been reported as 82° C. (Mallavadhani, U. V.; Sahu, G., Pterostilbene: A Highly Reliable Quality-Control Marker for the Ayurvedic Antidiabetic Plant ‘Bijasar’. Chromatographia 2003, 58, 307-312.). Efforts to improve the solubility of pterostilbene have focused on formulation approaches, such as by using cyclodextrins (LoI 2009).
Recently, cocrystals and polymorphs of pterostilbene have been reported in WO/2011/09372, which is herein incorporated by reference.